Tyrosinase-negative and tyrosinase-positive oculocutaneous albinisms are autosomal recessive disorders in which there is no pigment, or minimally- detectable pigment, in the skin, hair, or eyes. The incidence of albinism in the United States is approximately 1:18,000, and the black population shows a high incidence. We hypothesize that the tyrosinase-negative form results from mutation of the tyrosinase gene, and that the tyrosinase- positive form results from mutation of the genes which control the eumelanin synthetic pathway, distal to tyrosinase catalysis. We have isolated a human tyrosinase gene and a candidate gene (pmel 17-1), whose product may be involved in controlling the eumelanin biosynthesis. In a study of a recessively-inherited albino family, structural differences in the tyrosinase locus were noted in two of those affected, as contrasted with their normal brother. The primary objective of this proposal is to classify the kinds of mutation in tyrosinase and pmel 17-1 genes in tyrosinase-negative and tyrosinase-positive albinos, and to develop a nucleic acid probe for prenatal diagnosis and improved carrier detection. To this end, we will determine the function of the pmel 17-1 gene product in eumelanin biosynthesis and will characterize the genomic organization of both the human tyrosinase and pmel 17-1 loci. We will analyze the restriction fragment length polymorphisms of tyrosinase and pmel 17-1 genes in tyrosinase-negative and -positive albino DNA, respectively, and will compare the mRNA expression and tyrosinase and pmel 17-1 cDNA sequences in albinos with the normal counterpart. Finally, we will express normal and mutated tyrosinase and pmel 17-1 genes in albino melanocytes, to confirm that the mutations result in the inactivity of the enzymes. Once we have identified and classified the pathologic lesions of mutant genes, we will design nucleic acid probes for prenatal diagnosis and improved carrier detection of tyrosinase-negative and tyrosinase-positive oculocutaneous albinism.
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